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Section 1 Flashcards

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1
Q

In vitro studies

A

Identification of a new drug target
Screening for a lead compound

Target validation -> target identification -> lead compound ID -> Candidate Optimization

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2
Q

Pre-clinical Testing

A

Animal Testing
2-4 years
Tests: Efficacy, Selectivity, Mechanism

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3
Q

Clinical Testing: Phase I

A

Phase I: is it safe? What are the pharmacokinetics?

20-100 people

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4
Q

Clinical Testing: Phase II

A

Does it work in patients with the disease?
100-200 patients
Usually conducted in special clinical centers
Measures: safety and efficacy “proof of concept”

Phase II: have the highest rate of drug failures

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5
Q

Lipinski Rule of 5

A 
No more than 5 H-bond donors
No more than 10 H-bond acceptors
Molecular mass of less than 500 Da
Octane-water partition coefficient NOT greater than 5
 (Solute in octanol / solute in water)
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6
Q

Preclinical Testing

A

Tests acute toxicity: determines maximum tolerated dose
Determines dose that is lethal in 50% of animals

Subacute Toxicity:
- determines the biochemical and physiological effect

Effect on reproductive performance
Carcinogenic Potential
Mutagenic Potential

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7
Q

Limitations of Preclinical Testing

A

Expensive and time consuming (2-6 years)

Large number of animals needed
Extrapolations of therapeutic index Anand toxicity data from animals

Rare and adverse effects are unlikely to be detected in preclinical testing

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8
Q

Confounds to clinical testing:

A

Variable hx of disease = overcome by large population evaluated over time

Presence of other diseases/risk factors = over come by cross over technique

Subject/observer bias =

  • placebo responses = overcome by single blind, crossover design
  • observer bias = double-blind design
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9
Q

IND

A

Investigational new drug application filed with the FDA

Includes:

  • info on composition/source of drug
  • chemical information
  • all data from preclinical
  • proposed clinical trial plans
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10
Q

Phase I Clinical Trial

A

20-100 healthy volunteers

Effects of drug as function of dosage for expected toxicity

To find the maximum tolerated dose so that a dose can be recommended for phase II

Pharmacokinetics measured
- absorption, distribution, 1/2 life, metabolism, excretion

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11
Q

Dose Escalation Methods of a Phase I Clinical Trial

A

Amount of drug in dose is increased with each cohort added

  • each cohort is called a “dose cohort” (~10)
  • new dose cohort cannot be initiated before safety in previous cohort has been fully assessed

Modified Fibronacci Series: add previous dose to the current one to get the new dose

With dose increases, the action between 2 consecutive doses get smaller

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12
Q

Phase 0 Clinical Trial

A

To test to see how much of a drug is present in tumor, blood, tissue after one dose —> to see if the drug actually got INTO the tumor

To check whether there is a problem with how the drug is:
Absorbed, distributed, metabolized

Pharmacokinetics and dynamics

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13
Q

Phase II Clinical Trial

A

In patients with the targeted disease (n = 100)

To determine efficacy = proof of concept

Evaluates safety, tolerability, efficacy

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14
Q

Phase III Clinical Trial

A

Evaluated in larger patients (1000-6000)

Performed in settings similar to those anticipated for ultimate use of the drug

  • formulated as intended for the market
  • usually expensive due to large number of patients

Safety and Efficacy

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15
Q

NDA

A

New Drug Application

  • if phase III trial meets expectations, NDA is filled out to market agent
    (For biological, a BLA is filed)

Takes months/years for FDA to review
Number of subjects avg 5000

Priority review for breakthrough drugs -> accelerated approval might be granted

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16
Q

Orphan Drug Program

A

Gives incentives for drugs that treat rare disease
(If less than 200,000 puts or R+D costs do not expect to be recovered)

Eg. Gleevec - oral treatment for CML

Accelerated Approval of NDA: use surrogate endpoints for effectiveness
- bio markers that are likely to predict clinical benefits

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17
Q

Phase IV Clinical Trial

A

Post marketing surveillance begins
NDA approved

Delienate treatment risks, benefits and use under “actual use” conditions
Efficacy Study

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18
Q

Patent Rights

A

20 year term for a drug patent filed after 1995

  • sometimes the patents expire after the drug is approved

Post expiration of the patent = any company can produce the equivalent
- file a ANDA (abbreviated new drug application) to market a generic version

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19
Q

MW of drugs

A

100-1000 Da

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20
Q

Agonist

A

Drugs that mimic actions of endogenous compounds

Agonist interacts with receptor to produce a pharmacological response

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21
Q

Partial Agonist

A

Agonist that produces a partial response when the receptor is fully saturated

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22
Q

Inverse Agonism

A

Binds to the same receptor as an agonist but produces the opposite effect

Requires that the receptor has a basal level of activity in absence of ligand

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23
Q

Antagonist

A

Interferes with action of an agonist/partial agonist/inverse agonist by binding to the receptors

  • they bind to the receptor and do not produce a pharmacologic response
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24
Q

Total number of receptors on a cell determines…

A

Maximal drug effect that the drug might produce

E = [D] x Emax/[D] + EC50

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25
Binding of different agonists to the same receptor:
Plotted on semi log Sigmoidal curve EC50 corresponds to the inflection point on the graph Two drugs will show the same Emax, yet different EC50
26
Low EC50
High Potency | Less drug needed to reach half of maximal response
27
High EC50
Low potency Need more concentration to reach 1/2 max High drug is not desirable, since adverse effects are likely to increase
28
Potency Ratio
Differences in potency between two drugs EC50 of Drug A/EC50 of Drug B = potency ratio
29
What determines the efficacy of the drug?
Emax Agonist versus partial agonist behavior = PA shows lower efficacy
30
How are drugs selected?
On efficacy or Emax The amount of drug given is based on the determination of the potency factor
31
Antagonists
Drugs that block actions of endogenous agents Carry no activity Observing Effects: - plot dose-response curve of an agonist - determine how that curve is affected by differing antagonist concentrations
32
Competitive Antagonists
One whose effects can be overcome by adding more agonist Agonist and antagonist compete with one another Commonly observed if they have reversible binding property to receptor By adding more: - curve shifts to the right (EC50 increases) - Emax is unchanged Better antagonist = tighter binding to the receptor
33
Non Competitive Antagonists
Prevents agonist from reaching maximum effect Irreversible binding = like a covalent modification Antagonist bound receptors are effectively removed from the pool of agonist targets By adding more non-competitive antagonist: - Emax is reduced - EC50 remains unchanged Makes the agonist look like a PARTIAL agonist (Emax lowered, EC50 unchanged)
34
Space receptors
Increase sensitivity of tissue to the drug (use little bc the target is larger) Agonist can produce max response without binding to all of the available receptors
35
Irreversible Antagonists in Spare Receptor Situation
IA decrease the number of spare receptors - increase EC50 - Emax left unchanged Once all space receptors are quenched, further addition of antagonist no longer effects the EC50 - EC50 remains unchanged - Emax decreases
36
Therapeutic Dose
ED50
37
Lethal Dose
LD50 Toxic dose
38
Dose Response Curves
Difficult to construct when pharm response is an “either-or” event Inter-individuality limits the applicability of 1 dose-response relationship to another
39
Quantal Dose Response Curve
Y axis = number of individuals responding X axis = concentration of drug (log[D]) Median effective dose = 50% of individuals exhibit the quantal response
40
Therapeutic Index
Margin of safety to be expected for a drug Therapeutic Index = TD 50/ED 50 On Dose-Response Quantal Curve, it is the range of dose between TD50 and ED50
41
What is the major route of elimination in drugs?
Excreted through the kidney unchanged
42
Lipophillicity of most drugs:
Facilitates cross through membrane Renal excretion of lipophillic drugs are POOR due to reabsoportion through the tubular membranes
43
What is the 2nd Major Route of Drug Elimination?
Bio transformation of drugs in hydrophilic metabolites - making them more polar is critical for the termination of biological activity and excretion through the body
44
What are Phase I Reactions in Xenobiotic Metabolizing System?
Introduce/exposes a polar functional group - OH, COOH, NH2, SH on compound Enzymes that Catayzle Phase I Functionalization Rxns exist on ER membrane
45
What are Phase II Enzymes in Metabolism?
Phase II Rxns (Conjugation Reactions) Conjugation of compounds to yield even more polar conjugated Located in the cyto soul
46
Where is the main site of drug metabolism/biotransformation?
Liver = principal organ GI tract, lungs, skin, kidneys = secondary
47
Cytochrome 450
Involved in Phase I reactions Oxidative Rxns require: - molecular oxygen - NADPH - reducing agent - Cytochrome 450
48
CYPs
Large capacity to metabolize large number of diverse chemicals Not high specificity Major Form: CYP3A4
49
Phase II Conjugation Reactions in Drug Metabolism
Functional group by Phase I makes compound reactive - neutralize functional group, make more soluble Phase II - involve specific transferases located in the cytosol - couples a endogenous substance + exogenous HIGHLY POLAR NATURE OF CONJUGATES PROMOTE elimination
50
Glucuronidation (Phase II reaction of Metabolism)
Endogenous reactant = UDP-Glucuronic Acid Uses UDP-glucuronosyltransferase (UGT)
51
Glutathione Conjugation in Phase II Reactions
Major detoxification pathway - conjugates reactive electrophillic compounds with tripeptide glutathione Glutathione S Transferase Endogenous Reactant = Glutathione
52
Sulphation in Phase II Conjugation Reaction
Sulphotransferase | Endogenous reactant = PAPS
53
The metabolic products are...
Often less active than the parent drugs | - they might have enhanced ability (inactive prodrugs might convert to metabolically active drugs
54
Drug metabolism...
Increases clearance | Decreases 1/2 life
55
Before a New Drug Application...
Route of metabolism and enzymes involved must be known
56
Isoniazid (INH)
Is the exception where Phase II reactions precede Phase I reactions Acetylation (Phase II) occurs 1st Hydrolysis (Phase I) occurs 2nd
57
Induction of metabolizing Enzymes
Increases the number of enzymes Induces Cytochrome P450 gene (of which makes more enzyme) - increases metabolism rate of some drugs
58
Inhibiting Metabolizing Enzyme
Decreases the amount of enzymes Grapefruit juice Alcohol Might impair elimination of the drug, prolong its effects, increased incidence of drug toxicity
59
Liver dysfunction
Affects the liver function and diminishes they metabolism of some drugs - increases the half life of drugs
60
As one ages, there is..
``` Decrease in: liver mass Hepatic enzyme activity Hepatic blood flow P450 activity ``` Females: decreased oxidation of estrogens and benzodiazepines
61
Oral Route Absorption of Drugs
Absorption of drug from H2O across the GI epithelium | GI -> Blood
62
Drug Lipophillicity
Factor involved in absorption - lipid/water partition coefficient is the best predictor of drug entry measured by octanol/water - higher the coefficient means that the drug will leave the water phase and cross into the GI epithelium
63
PkA or Ka of a adrug
Factor involved in absorption Most drugs are weak bases or weak acids
64
Uncharged weak acid
Protonated form Can move across the biological membrane
65
Uncharged form of weak base
Unprotonated form Can move across the biological membrane
66
Lipid/Water Partition Coefficient
Best predictor of drug entry into body If above one, or higher, the drug will more readily leave the water phase and cross the GI epithelium
67
10 (pH-pKa) =
[A-]/[HA] For carboxlyic acids, they are ionic in the deprotonated state.
68
1O (pH-pKa) = (for amines)
[B]/[BH+]
69
Partitioning of Drug
Distribution of a drug will proceed until the uncharged form of drug achieves equal concentration in both water compartments At equilibrium, the total drug concentration is higher in compartment with higher pH-dependent ionization. -> if it is ionized, it is stuck in place!
70
Oral Bioavailability of a drug is:
Fraction of the drug that gains access to systemic circulation in chemical all unaltered forms - if it is absorbed well and survives the liver metabolism Mouth -> GI -> liver (1st pass metabolism)
71
Infusion Rate
R = CL (body) x CL (plasma)
72
Half Life Equation
T1/2 = .693 x Vd / CL(body) Vd = L/kg This means that you need to correct for Kg of the patient Vd = 1.5L/Kg x 70kg
73
What is the time for a drug to reach steady state concentration?
Four 1/2 lives Eg: (8 hr half-life)(4) = 32 hours to reach steady state
74
To create an IV regimen, you begin with twice the effective dose of the drug. Then what?
Repeat with the effective dose every 1/2 life of the drug. Only works if: - half-life is between 8-24 hrs - 2 fold fluctuation in the drug is acceptable Example: Loading dose = 500 mg Maintenance Dose = 250 mg/8 hours
75
Switch from IV -> Oral Considerations:
Maintenance Dose in IV is 100mg/2x day Oral Dose with a bioavailability of 50% = 200mg/2x
76
Fixed Dose and Fixed Time Regimen = most common pattern of administration
Drugs are eliminated exponentially - some of the 1st dose is present at the time of the 2nd dose Drug accumulates until its concentration increases to a SS point where the rate of input = rate of output
77
When is steady state reached?
After 4 half lives, the amount of drug lost during the dosing interval is exactly what is being put in
78
Volume of Distribution (Vd)
Vd must be normalized by body weight (L/Kg) ``` Vd = total amount of drug in the body/plasma concentration of drug Vd = Ab / Cpl ```
79
Clearance (CL)
Volume of plasma from which all drug is removed CL(body) = L/hr, mL/min - should be normalized for body weight CL(renal)+CL(hepatic)=CL(body)
80
Clearance of drug at an organ
CLorgan = Organ Plasma Flow (OPF) x Extraction Ratio (ER) Extraction Ratio: fractional decline in drug concentration from arterial->venous side of the organ
81
Half Life
Time it takes for plasma concentration or amount of drug in body to be reduced by half T1/2 = .693 x Vd/CLbody As Vd goes up, so does the half-life
82
IV infusion
Continuous administration at a constant rate Upon infusion, plasma concentration rises until the rate of loss = rate of input - Cpl-ss = therapeutic level / efficacious level
83
At the steady state, the rate of the infusion =
R = CLbody x Cpl-s
84
Increase in Rate, changes SS-level in what way?
2R will cause the steady state level to double Therefore, increasing rate does not allow SS to be reached faster 2 in 2R controls where you end up, not how fast you get there.

Pharm (6 decks)

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